We propose to develop automated, combinatorial ATRP and RAFT polymerization techniques for the synthesis of a library of >1500 structurally distinct core-shell hairy nanoparticles for short interfering RNA (siRNA) delivery. The polymers will be synthesized using controlled/living radical polymerization (CRP) techniques to enable control over architecture, molecular weight, polydispersity, and physical properties. While siRNA has great therapeutic potential to treat various diseases, delivery remains a huge challenge and is at the present time, the key roadblock preventing commercialization of siRNA to treat disease. We therefore propose to develop a library of core-shell hairy nanoparticles with a diameter of 10-80 nm, a cationic core, and a tunable and functionalizable shell for siRNA delivery. High-throughput synthesis, purification, measurement of MW and particle diameter, complexation with siRNA, and in vitro screening for delivery of siRNA will be performed in series. Through analysis, we anticipate that structural motifs that are important for complexation and delivery will emerge. We will seek to understand structure-function relationships by analysis and comparison of the best performing hairy nanoparticles. As our proposal employs combinatorial, automated high-throughput synthesis and selection of structured polymers for siRNA delivery, the resulting materials have the potential to overcome delivery and targeting challenges, which may lead to realized therapies for various diseases. PUBLIC HEALTH RELEVANCE: Short interfering RNA (siRNA) has great therapeutic potential to treat various diseases including cancer, arthritis, CNS diseases, retinopathy, asthma, Parkinson's disease and others, but delivery remains as the key roadblock preventing successful utilization of siRNA to treat disease. Our proposal employs combinatorial, automated high-throughput synthesis and evaluation of structured polymers for with control over molecular weight and architecture for siRNA delivery. The resulting polymers have the potential to overcome delivery and targeting challenges, which may lead to realized therapies for various diseases.